In addition to functioning as genetic transcripts, RNA molecules play structural and even catalytic roles. Depending on their specific cellular roles, RNA molecules can be largely single stranded or adopt specific tertiary structures. A variety of proteins are necessary to assure the correct folding of RNA molecules and to maintain or modify their specific secondary or tertiary structures. Among these proteins are the RNA helicases of the DEAD-box family and related families (de la Cruz et al., Trends Biochem. Sci., 1999, 24, 192-198). These are involved in various aspects of RNA metabolism, including nuclear transcription, pre-mRNA splicing, ribosome biogenesis, nucleocytoplasmic transport, translation, RNA decay and gene expression. Although generally assumed to be a double-stranded RNA, the substrate might also be an RNA-protein complex. Some investigators therefore refer to these proteins as RNA-dependent NTPases or RNA unwindases, to distinguish them from the processive DNA helicases (de la Cruz et al., Trends Biochem. Sci., 1999, 24, 192-198).
More recently, helicases have been implicated in the process of posttranscriptional gene silencing (PTGS), a form of RNA-mediated interference (Cogoni and Macino, Science, 1999, 286, 2342-2344). In this process, the helicase is required to separate the double-stranded DNA before any hybridization and silencing mechanism can be initiated.
The DEAD and DEAH helicase families are closely related helicase groups with their names derived from the sequence of the Walker B motif (DEAD=Asp-Glu-Ala-Asp; DEAH=Asp-Glu-Ala-His) (reviewed in (de la Cruz et al., Trends Biochem. Sci., 1999, 24, 192-198)). The DEXH family is a variation on the DEAH family wherein the third amino acid in the DEAH sequence is variable.
Helicase-moi (also known as KIAA0928, HERNA, delta-K12H4.8 homologue and HEMBA1004199) is a recently discovered helicase gene that encodes a protein belonging to the DEXH-box helicase family (Matsuda et al., Biochim. Biophys. Acta, 2000, 1490, 163-169; Nagase et al., DNA Res., 1999, 6, 63-70; Provost et al., Proc. Natl. Acad. Sci. U.S.A., 1999, 96, 1881-1885). In human tissues, helicase-moi is expressed in brain, lung, liver, pancreas and kidney and the gene has been localized to chromosome 14q31 (Matsuda et al., Biochim. Biophys. Acta, 2000, 1490, 163-169). Other genes that have been mapped to 14q31 are potential targets involved in Krabble disease, ovarian cancer, and Graves' disease (Matsuda et al., Biochim. Biophys. Acta, 2000, 1490, 163-169).
Helicase-moi has been found to interact strongly with the enzyme 5-lipoxygenase which plays a central role in cellular leukotriene synthesis (Provost et al., Proc. Natl. Acad. Sci. U.S.A., 1999, 96, 1881-1885). Since leukotrienes are mediators of inflammation, selective inhibition of potential regulators of leukotriene synthesis, such as helicase-moi, may prove to be an efficient strategy with which to derive treatments for inflammatory disorders. To date, specific inhibitors for helicase-moi have yet to be developed or identified. Consequently, there remains a long felt need for agents capable of effectively and selectively inhibiting the function of helicase-moi.
Antisense technology is emerging as an effective means for reducing the expression of specific gene products and may therefore prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications for the modulation of expression of helicase-moi.
The present invention provides compositions and methods for modulating expression of helicase-moi.